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serum levels 90 minutes after LPS infusion were found to be about 50%
lower for the β-PGG-treated rats compared to positive control (just LPS).
(Fig. 6. 22).
However, many symptoms of septic shock were still detected in the
β-PGG treated rats. The glucose levels for the LPS/β-PGG treated
animals (170 mg/dL) were similar to the LPS-only rats (155 mg/dL) and
both were higher than the saline-only control rats (55 mg/dL). Also, the
animals treated with β-PGG suffered from increased heart rate and
hypotension. These results perhaps could be attributed to the IL-
1β−inducing properties of β-PGG. Whereas β-PGG managed to lower
the LPS-induced TNFα levels, the LPS/β-PGG rats had either similar or
higher IL-1β levels compared to the positive controls. In the end,
however, a promising new lead compound for the treatment of septic
shock may have been identified.
Interestingly, β-PGG also has been described as an efficient inhibitor
(IC
50
2.1μM) of the binding of vascular endothelial growth factor
(VEGF), a critical angiogenic molecule, to its receptor KDR/Flk-1 (Lee
et al.
, 2004). Although β-PGG modified the microvasculature of
endothelial cells, it did not directly influence the proliferation of cancer
cells (HT1080 human fibrosarcoma and DU-145 human prostate
carcinoma).
6.5.2 Dimeric gallotannin analogues as lipid A antagonists
The simple gallotannin β-PGG (
66
) managed to lower TNFα levels
in
vitro
and
in vivo
, but did not alleviate the symptoms of septic shock in
live rats. It may be possible that these symptoms could be lessened by
decreasing the levels of the other proinflammatory cytokine generated,
IL-1β, whose concentration was equal to or higher in the β-PGG-
administered rats compared with the animals treated only with LPS. To
this end, five analogues of the lipid A agonist
81
were studied with the
intent of identifying a lead candidate that was ineffective at promoting
secretion of both TNFα and IL-1β. Specifically, the linker unit that joins
the two tetragalloylglucose end caps (= binding units?) of
81
was
targeted for modification. If the tetragalloylglucose components of
81
